There is a significant sex-bias in lung cancer with males showing increased mortality compared to females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex-bias in humanized mice, with male patient-derived xenograft (PDX) lung tumors being more progressive and deadlier than female PDX lung tumors, we identified mouse tumor models of lung cancer with the same sex-bias. This sex-bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex-bias in growth and lethality required intact ovaries, functional innate natural killer (NK) cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anti-cancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-BCL-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the BCL-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer.

中文翻译：

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先天免疫系统和 TRAIL-BCL-XL 轴介导肺癌的性别偏倚，并赋予女性治疗脆弱性


肺癌存在显着的性别偏见，与女性相比，男性的死亡率更高。对这些差异的更好的机制理解可能有助于确定治疗靶点，以便针对每种性别个性化癌症治疗。在观察到人源化小鼠的明显性别偏倚后，雄性患者来源的异种移植物 （PDX） 肺肿瘤比雌性 PDX 肺肿瘤更具进展性和更致命，我们确定了具有相同性别偏倚的肺癌小鼠肿瘤模型。在乳腺癌、结肠癌、黑色素瘤和肾癌的模型中未观察到这种性别偏倚。在体内，生长和致死性的性别偏倚需要完整的卵巢、功能性先天自然杀伤 （NK） 细胞和单核细胞/巨噬细胞，以及激活受体 NKG2D。当与卵巢完整的雌性小鼠的血清一起培养时，离体细胞培养模型通过 TRAIL-BCL-XL 轴对 NKG2D 介导的 NK 细胞和巨噬细胞杀伤的抗癌作用敏感。在侧腹和原位模型中，BCL-XL 抑制剂 navitoclax （ABT-263） 改善了雌性小鼠的肿瘤生长控制，并需要 NK 细胞、巨噬细胞和 TRAIL 信号通路。这项研究表明，navitoclax 和 TRAIL 通路激动剂可用作个性化疗法，以改善女性肺癌患者的预后。